Hypothalamic neuropeptide Y levels in weaning offspring of low-protein malnourished mother rats.

Maternal low-protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Hypothalamic neuropeptides are decisively involved in the central nervous regulation of body weight and metabolism. We investigated neuropeptide Y (NPY) in distinct hypothalamic nuclei in the offspring of LP mother rats at the end of the critical hypothalamic differentiation period (20th day of life). Weanling LP offspring were underweight (P< 0.001) and hypoinsulinaemic (P< 0.05), while leptin levels were unchanged. NPY was significantly increased in the paraventricular hypothalamic nucleus (PVN) (P< 0.01) and lateral hypothalamic area (P< 0.05) in LP offspring. In contrast, NPY was unchanged in the ventromedial hypothalamic nucleus (VMN). These observations indicate a leptin-independent stimulation of the orexigenic ARC-PVN axis in undernourished LP rats at weaning. Furthermore a disturbed NPYergic regulation of the VMN is suggested, possibly contributing to alterations of the hypothalamic regulation of body weight and metabolism in LP offspring during life.

Malformations of hypothalamic nuclei in hyperinsulinemic offspring of rats with gestational diabetes.

Insulin is a potent modulator of central nervous development and is suggested to influence the differentiation and maturation of hypothalamic structures involved in the regulation of body weight and metabolism. Hyperinsulinemic offspring of mothers with impaired glucose tolerance during pregnancy (gestational diabetes, GD) have an increased risk to develop overweight and diabetes mellitus during life, while the underlying pathophysiological mechanisms are still unknown. To investigate the effects of perinatal hyperinsulinism on the organization of hypothalamic regulators of body weight and metabolism, GD was induced in rats by application of streptozotocin on the day of conception (25 mg/kg, i.p.). On the 21st day of life, offspring of GD rats were overweight (p < 0.05) and hyperinsulinemic (p < 0.01). Using computer-assisted morphometric measurements, significantly decreased mean areas of neuronal nuclei and neuronal cytoplasm within the paraventricular hypothalamic nucleus (PVN; p < 0.01) and the ventromedial hypothalamic nucleus (VMN; p < 0.05) were observed in GD offspring. Analysis of topographically distinct parts revealed that these alterations particularly occurred in the parvocellular part of the PVN, as well as in the anterior, central, and dorsomedial part of the VMN. No morphometric alterations were found within the lateral hypothalamic area and the dorsomedial hypothalamic nucleus. In the arcuate hypothalamic nucleus, the mean area of neuronal cytoplasm was decreased (p < 0.05), while the number of neurons expressing tyrosine hydroxylase was clearly elevated (p < 0.002). For astrocytes, a tendency towards an increased glia/neuron ratio was observed in the periventricular hypothalamic area. These observations suggest disturbed differentiation and organization of distinct hypothalamic nuclei and subnuclei, respectively, in hyperinsulinemic offspring of GD rats, possibly leading to dysfunctions of hypothalamic regulators of body weight and metabolism which might contribute to the lifelong increased risk to develop overweight and diabetogenic disturbances.

Cholecystokinin-8S levels in discrete hypothalamic nuclei of weanling rats exposed to maternal protein malnutrition.

Perinatal malnutrition and growth retardation at birth are suggested to be important risk factors for the development of overweight and syndrome X in later life. Underlying mechanisms are unknown. Body weight and food intake are regulated, e.g. by hypothalamic neuropeptidergic systems which are thought to be highly vulnerable to persisting malorganization due to perinatal malnutrition. To investigate possible consequences for hypothalamic cholecystokinin-8S (CCK-8S) in the offspring, pregnant Wistar rats were fed an 8% protein diet during pregnancy and lactation (low-protein group; LP) while control mothers (CO) received a 17% protein isocaloric standard diet. LP offspring displayed underweight at birth (P < 0.05) and during suckling (P < 0.001), while leptin levels were not altered. At weaning, under basal conditions CCK-8S was decreased in LP offspring in the paraventricular hypothalamic nucleus and arcuate hypothalamic nucleus (P < 0.05), as well as in the dorsomedial hypothalamic nucleus, lateral hypothalamic area and ventromedial hypothalamic nucleus (P < 0.01). In summary, these data indicate (1) an inhibition of the satiety peptide CCK-8S in main regulators of body weight and food intake in low-protein malnourished newborn rats; (2) no direct relationship of hypothalamic CCK-8S to circulating leptin at this age; and (3) no neurochemical signs of hypothalamic CCKergic dysregulation in this animal model at the age of weaning.

Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats.

Catecholamines are essential organizers of the developing brain. Throughout life, they are involved, e.g., in the regulation of body weight and metabolism by specific hypothalamic nuclei, which are suggested to be highly vulnerable to maternal gestational hyperglycemia. By application of streptozotocin (30 mg/kg, i.p.) gestational diabetes (GD) was induced in female rats. On the 1st day of life, male GD offspring were underweight (P<0.05) and hyperglycemic (P<0.05), while on the 21st day of life decreased body weight (P<0.001) and elevated pancreatic insulin (P<0.01) were observed. Using HPLC with electrochemical detection, hypothalamic catecholamines were determined in the newborns, and quantitative immunocytochemistry for tyrosine hydroxylase (TH) was performed. At birth, a tendency towards increased levels of norepinephrine (NE) and dopamine (DA) in the whole hypothalami of GD offspring was observed. In the 21-day-old offspring of GD mothers, NE was significantly increased in the ventromedial hypothalamic nucleus (VMN; P<0.05) and the lateral hypothalamic area (LHA; P<0.05), while DA was significantly elevated in the paraventricular hypothalamic nucleus (PVN; P<0.05) and the LHA (P<0.05). The NE/DA-ratio was found to be decreased in the PVN of GD offspring (P<0.01). Moreover, numerical density of TH-positive neurons was clearly increased within the parvocellular division of the PVN (P<0.0001) as well as in the periventricular hypothalamic area (PER; P<0.05). These data suggest specific alterations of catecholaminergic systems within hypothalamic regulators of body weight and metabolism during early development in the offspring of gestational diabetic mother rats.

Hypothalamic insulin and neuropeptide Y in the offspring of gestational diabetic mother rats.

The offspring of diabetic mothers is at increased risk to develop obesity and diabetogenic disturbances during life. Pathophysiological mechanisms responsible are unclear. Neuropeptide Y (NPY) is an important hypothalamic stimulator of food intake and body weight gain, and its levels are decreased by elevated insulin. In neonatally hyperinsulinaemic offspring of diabetic mother rats, hypothalamic insulin level was significantly increased at birth (p < 0.01). At weaning, i.e. at the end of the critical hypothalamic differentiation period, a significantly increased number of NPY-positive neurons (p < 0.01) appeared in the arcuate hypothalamic nucleus. In conclusion, an increase in the number of NPYergic neurons in the hypothalamus, possibly due to hypothalamic malformation and/or perinatally acquired hypothalamic insulin resistance, might contribute to the development of obesity and metabolic disturbances in the offspring of diabetic mothers.